This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Background. Immune activation levels were reported to be the best predictor of disease progression in HIV-infected patients. However, there is no direct proof that induction of immune activation during chronic HIV/SIV infection increases viral replication. We therefore experimentally induced immune activation in SIVagm-infected African green monkeys (AGMs) a species resistant to AIDS. Methods. Four SIVagm-infected AGMs were treated with ONTAK (Denileukin Diftitox) during chronic infection to deplete CD4+CD25+ T regulatory cells (Tregs). The dynamics of VL were measured by real-time PCR. Major T-cell populations and subsets were measured by flow-cytometry and the dynamics of pro-inflammatory cytokines in plasma was quantified by Luminex. Results. Ontak did not induce a reduction in the number or function of Tregs in chronically SIV-infected AGMs. However, ONTAK administration induced a significant increase in immune activation in all animals as illustrated by the increases in [unreadable]HLA-DR and CD69 expression on both CD4+ and CD8+ T-cells. Increased CD4+ T-cell proliferation (Ki-67) was also observed, resulting in significant increases in the pool of peripheral CD4+ T-cells. Furthermore, significant increases in the levels of proinflammatory cytokines were observed after ONTAK administration. These changes persisted for three weeks after the initiation of each treatment and resulted in significant increases (2-4 log) in VLs in all animals. Conclusion. We report the first successful experiment aimed at inducing immune activation in a natural host of SIV. Also, our results provide for the first time compelling proof-of concept that induction of immune activation during chronic SIV infection results in significant increases in viral replication, thus supporting the concept that immune activation is a key factor in disease progression during HIV/SIV infection.